A considerable amount of evidence implicates the cannabinoid system in the mediation and/or modulation of the behavioral effects of ethanol. An opioid peptide link has been suggested in this process though the relative involvement of specific opioid receptors in the CB1 receptor-induced modulation of ethanol drinking is not known. Based on recent data from our work and from others it is hypothesized that CB1 receptors exert a positive control over ethanol self-administration, and that this influence is mediated in part by a CB1 receptor-induced regulation of opioid peptide release. The projects in this proposal are designed to further characterize the effects of cannabinoid manipulations on ethanol consumption, and to evaluate the relative involvement of mu, delta and kappa opioid receptors (and their associated endogenous peptide ligands) in the modulation of ethanol intake by CB1 receptors. Specific Aim 1 will evaluate the ability of selective opioid receptor antagonists to reverse CB1 agonist-induced increases in ethanol self-administration. Specific Aim 2 will characterize the effects of altered brain endocannabinoid neurotransmission on ethanol self-administration, and will investigate the influence of each class of opioid receptor in these effects. Inhibition of endocannabinoid reuptake and hydrolysis, respectively, will be used in these experiments to increase interstitial endocannabinoid levels, which has been found in our laboratory to increase ethanol self-administration. Specific Aim 3 will investigate alterations in ethanol self-administration produced by cannabinoid and opioid manipulations in three brain regions: the nucleus accumbens shell, the ventral tegmental area and the central nucleus of the amygdala. In vivo microdialysis will be used in these experiments to provide direct evidence for a CB1 receptor modulation of opioid peptide release. Finally, Specific Aim 4 will examine the effects produced by CB1 receptor manipulations in an animal model of ethanol relapse in an effort to evaluate the potential therapeutic utility of CB1 antagonists for the treatment of alcoholism.